An intracardiac electrogram model to bridge virtual hearts and implantable cardiac devices

Virtual heart models have been proposed to enhance the safety of implantable cardiac devices through closed loop validation. To communicate with a virtual heart, devices have been driven by cardiac signals at specific sites. As a result, only the action potentials of these sites are sensed. However, the real device implanted in the heart will sense a complex combination of near and far-field extracellular potential signals. Therefore many device functions, such as blanking periods and refractory periods, are designed to handle these unexpected signals. To represent these signals, we develop an intracardiac electrogram (IEGM) model as an interface between the virtual heart and the device. The model can capture not only the local excitation but also far-field signals and pacing afterpotentials. Moreover, the sensing controller can specify unipolar or bipolar electrogram (EGM) sensing configurations and introduce various oversensing and undersensing modes. The simulation results show that the model is able to reproduce clinically observed sensing problems, which significantly extends the capabilities of the virtual heart model in the context of device validation

Topogenesis and cell surface trafficking of GPR34 are facilitated by positive-inside rule that effects through a tri-basic motif in the first intracellular loop

AbstractProtein folding, topogenesis and intracellular targeting of G protein-coupled receptors (GPCRs) must be precisely coordinated to ensure correct receptor localization. To elucidate how different steps of GPCR biosynthesis work together, we investigated the process of membrane topology determination and how it relates to the acquisition of cell surface trafficking competence in human GPR34. By monitoring a fused FLAG-tag and a conformation-sensitive native epitope during the expression of GPR34 mutant panel, a tri-basic motif in the first intracellular loop was identified as the key topogenic signal that dictates the orientation of transmembrane domain-1 (TM1). Charge disruption of the motif perturbed topogenic processes and resulted in the conformational epitope loss, post-translational processing alteration, and trafficking arrest in the Golgi. The placement of a cleavable N-terminal signal sequence as a surrogate topogenic determinant overcame the effects of tri-basic motif mutations and rectified the TM1 orientation; thereby restored the conformational epitope, post-translational modifications, and cell surface trafficking altogether. Progressive N-tail truncation and site-directed mutagenesis revealed that a proline-rich segment of the N-tail and all four cysteines individually located in the four separate extracellular regions must simultaneously reside in the ER lumen to muster the conformational epitope. Oxidation of all four cysteines was necessary for the epitope formation, but the cysteine residues themselves were not required for the trafficking event. The underlying biochemical properties of the conformational epitope was therefore the key to understand mechanistic processes propelled by positive-inside rule that simultaneously regulate the topogenesis and intracellular trafficking of GPR34

The effect of cell-to-cell variations and thermal gradients on the performance and degradation of lithium-ion battery packs

The performance of lithium-ion battery packs are often extrapolated from single cell performance however uneven currents in parallel strings due to cell-to-cell variations, thermal gradients and/or cell interconnects can reduce the overall performance of a large scale lithium-ion battery pack. In this work, we investigate the performance implications caused by these factors by simulating six parallel connected batteries based on a thermally coupled single particle model with the solid electrolyte interphase growth degradation mechanism modelled. Experimentally validated simulations show that cells closest to the load points of a pack experience higher currents than cells further away due to uneven overpotentials caused by the interconnects. When a cell with a four times greater internal impedance was placed in the location with the higher currents this actually helped to equalise the cell-to-cell current distribution, however if this was placed at a location furthest from the load point this would cause a ~6% reduction in accessible energy at 1.5 C. The influence of thermal gradients can further affect this current heterogeneity leading to accelerated aging. Simulations show that in all cases, cells degrade at different rates in a pack due to the uneven currents, with this being amplified by thermal gradients. In the presented work a 5.2% increase in degradation rate, from -7.71 mWh/cycle (isothermal) to - 8.11 mWh/cycle (non-isothermal) can be observed. Therefore, the insights from this paper highlight the highly coupled nature of battery pack performance and can inform designs for higher performance and longer lasting battery packs

Gut microbiome dysbiosis in at-risk versus low-risk stroke adults

"Healthy brain aging has been a significant focus in older adults. Lifestyle changes such as diet and exercise have been implemented by adults to avoid brain related disease processes such stroke and Alzheimer’s disease. Stroke risk factors such as high BMI, hypertension, diabetes, and the presence of ApoE4 gene have been explored in hopes to find interventions targeted to promote more healthy brain aging. Currently there is a knowledge gap on how interventions can promote healthy brain aging. Targeting the bidirectional gut-brain axis by manipulating the gut microbiome can be a possible intervention to promote brain health."--Introduction

Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246

TP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific mutp53 proteins gain oncogenic functions (GOFs) distinct from the tumor suppressor activity of the wild-type protein. Tumor-associated macrophages (TAMs), a hallmark of solid tumors, are typically correlated with poor prognosis. Here, we report a non-cell-autonomous mechanism, whereby human mutp53 cancer cells reprogram macrophages to a tumor supportive and anti-inflammatory state. The colon cancer cells harboring GOF mutp53 selectively shed miR-1246-enriched exosomes. Uptake of these exosomes by neighboring macrophages triggers their miR-1246-dependent reprogramming into a cancerpromoting state. Mutp53-reprogammed TAMs favor anti-inflammatory immunosuppression with increased activity of TGF-β. These findings, associated with poor survival in colon cancer patients, strongly support a microenvironmental GOF role for mutp53 in actively engaging the immune system to promote cancer progression and metastasis

Inhibition of TNF receptor p55 by a domain antibody attenuates the initial phase of acid-induced lung injury in mice

Background: Tumor necrosis factor-α (TNF) is strongly implicated in the development of acute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has been hampered by its complex biology. TNF signals through two receptors, p55 and p75, which play differential roles in pulmonary edema formation during ARDS. We have recently shown that inhibition of p55 by a novel domain antibody (dAb™) attenuated ventilator36 induced lung injury. In the current study we explored the efficacy of this antibody in mouse models of acid-induced lung injury, to investigate the longer consequences of treatment. Methods: We employed two acid-induced injury models, an acute ventilated model and a resolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally or intranasally with p55-targeting dAb or non-targeting ‘dummy’ dAb, 1 or 4 hours before acid instillation. Results: Acid instillation in the dummy dAb group caused hypoxemia, increased respiratory system elastance, pulmonary inflammation and edema in both the ventilated and resolving models. Pretreatment with p55-targeting dAb significantly attenuated physiological markers of ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in the ventilated model, with signs that altered cytokine production and leukocyte recruitment persisted beyond the very acute phase. Conclusions: These results demonstrate that the p55-targeting dAb attenuates lung injury and edema formation in models of ARDS induced by acid aspiration, with protection from a single dose lasting up to 24 hours. Together with our previous data, the current study lends support towards the clinical targeting of p55 for patients with, or at risk of ARDS

Interventions to increase the consumption of water among children

The aim of this study was to conduct a systematic review and meta-analysis on the effectiveness of interventions to increase children's water consumption. A systematic literature search was conducted in seven electronic databases. Studies published in English before 18 February 2019 that evaluated any type of intervention that measured change in water consumption among children aged 2 to 12 years by applying any type of design were included. Of the 47 interventions included in the systematic review, 24 reported a statistically significant increase in water consumption. Twenty-four interventions (17 randomized controlled trials and seven studies with other controlled designs) were included in the meta-analysis. On average, children in intervention groups consumed 29 mL/d (confidence interval [CI] = 13–46 mL/d) more water than did children in control groups. This effect was larger in eight interventions focused specifically on diet (MD = 73 mL/d, CI = 20–126 mL/d) than in 16 interventions focused also on other lifestyle factors (MD = 15 mL/d, CI = 1–29 mL/d). Significant subgroup differences were also found by study setting and socioecological level targeted but not by children's age group, intervention strategy, or study design. In conclusion, there is evidence that, on average, lifestyle interventions can lead to small increases in children's daily water consumption. More research is needed to further understand th

Inertial Sensing to Determine Movement Disorder Motion Present before and after Treatment

There has been a lot of interest in recent years in using inertial sensors (accelerometers and gyroscopes) to monitor movement disorder motion and monitor the efficacy of treatment options. Two of the most prominent movement disorders, which are under evaluation in this research paper, are essential tremor (ET) and Parkinson’s disease (PD). These movement disorders are first evaluated to show that ET and PD motion often depict more (tremor) motion content in the 3–12 Hz frequency band of interest than control data and that such tremor motion can be characterized using inertial sensors. As well, coherence analysis is used to compare between pairs of many of the six degrees-of-freedom of motions under evaluation, to determine the similarity in tremor motion for the various degrees-of-freedom at different frequency bands of interest. It was quite surprising that this coherence analysis depicts that there is a statistically significant relationship using coherence analysis when differentiating between control and effectively medicated PD motion. The statistical analysis uncovers the novel finding that PD medication induced dyskinesia is depicted within coherence data from inertial signals. Dyskinesia is involuntary motion or the absence of intended motion, and it is a common side effect among medicated PD patients. The results show that inertial sensors can be used to differentiate between effectively medicated PD motion and control motion; such a differentiation can often be difficult to perform with the human eye because effectively medicated PD patients tend to not produce much tremor. As well, the finding that PD motion, when well medicated, does still differ significantly from control motion allows for researchers to quantify potential deficiencies in the use of medication. By using inertial sensors to spot such deficiencies, as outlined in this research paper, it is hoped that medications with even a larger degree of efficacy can be created in the future

Subarachnoid haemorrhage with negative initial neurovascular imaging: a systematic review and meta-analysis

Abstract: Background: In patients with spontaneous subarachnoid haemorrhage (SAH), a vascular cause for the bleed is not always found on initial investigations. This study aimed to systematically evaluate the delayed investigation strategies and clinical outcomes in these cases, often described as “non-aneurysmal” SAH (naSAH). Methods: A systematic review was performed in concordance with the PRISMA checklist. Pooled proportions of primary outcome measures were estimated using a random-effects model. Results: Fifty-eight studies were included (4473 patients). The cohort was split into perimesencephalic naSAH (PnaSAH) (49.9%), non-PnaSAH (44.7%) and radiologically negative SAH identified on lumbar puncture (5.4%). The commonest initial vascular imaging modality was digital subtraction angiography. A vascular abnormality was identified during delayed investigation in 3.9% [95% CI 1.9–6.6]. There was no uniform strategy for the timing or modality of delayed investigations. The pooled proportion of a favourable modified Rankin scale outcome (0–2) at 3–6 months following diagnosis was 92.0% [95% CI 86.0–96.5]. Complications included re-bleeding (3.1% [95% CI 1.5–5.2]), hydrocephalus (16.0% [95% CI 11.2–21.4]), vasospasm (9.6% [95% CI 6.5–13.3]) and seizure (3.5% [95% CI 1.7–5.8]). Stratified by bleeding pattern, we demonstrate a higher rate of delayed diagnoses (13.6% [95% CI 7.4–21.3]), lower proportion of favourable functional outcome (87.2% [95% CI 80.1–92.9]) and higher risk of complications for non-PnaSAH patients. Conclusion: This study highlights the heterogeneity in delayed investigations and outcomes for patients with naSAH, which may be influenced by the initial pattern of bleeding. Further multi-centre prospective studies are required to clarify optimal tailored management strategies for this heterogeneous group of patients